2-(arylalkenyl)azacycloalkane derivatives as ligands for sigma receptors

ABSTRACT

New 2-(arylalkenyl)azacycloalkane derivatives which are ligands for sigma receptors, of the formula (I) ##STR1## in which: Ar is aryl or heteroaryl, optionally mono- to trisubstituted, 
     m has the value 1 or 2, 
     n has the value 1 to 3, 
     R is phenyl, or cycloalkyl containing 3 to 7 carbon atoms, 
     their isomers and their addition salts. Medicinal drugs which are antipsychotic agents and are useful in gastroenterology.

This application is a 371 of PCT/FR94/01439, filed Dec. 9, 1994.

FIELD OF THE INVENTION

This invention relates to new compounds derived from2-(arylalkenyl)azacycloalkanes which are in vitro ligands for sigma (σ)receptors and are potentially useful in the treatment ofgastrointestinal complaints and in the treatment of neurologicaldisorders and/or psychotic states.

TECHNOLOGICAL BACKGROUND OF THE INVENTION

European Patent Application 362,001 describes α,α-disubstitutedN-cycloalkylalkylamines having specific affinity for sigma (σ) receptorsand which are useful in the treatment of psychoses and gastrointestinalcomplaints, of the formula ##STR2## in which: R₁ and R₅ are phenyl, R₂is alkyl, R₃ is hydrogen or low-molecular-weight alkyl, R₄ iscycloalkyl, m is 1 or 2.

European Patent Application 445,013 describes N-cycloalkylalkylamineshaving specific affinity for σ receptors and which are useful in thetreatment of psychoses and gastrointestinal complaints, of the formula##STR3## in which: R₁ is a furyl or thienyl radical or alternatively aphenyl radical, provided that Q is 1,2-cyclopropanediyl, R₂ islow-molecular-weight alkyl, R₃ is hydrogen or low-molecular-weightalkyl, m has the value 1 or 2, R₄ is cycloalkyl-CH(CH₂)_(n) in which nis from 2 to 5, R₅ is phenyl or thienyl, Q is 1,2-ethylenediyl or1,2-cyclopropanediyl.

Although displaying an affinity for the same types of receptors as thecompounds of this invention, the amines disclosed in these two documentsdiffer in terms of their structure, which is that of amines in which thenitrogen atom is not included in a cycloalkane sequence.

PCT Application WO 91/03243 includes a description of1-cycloalkylpiperidines having specific antagonist activity toward σreceptors and which are useful in the treatment of psychoses anddyskinesias, of the formula ##STR4## in which, preferably: X is C═O,CHOH or O; and/or m is 0; and/or n and p are 1; and/or R₃ -R₅ are H;and/or Ar is phenyl, optionally substituted by halogens, OCH₃, NH₂, NO₂or another phenyl group, a and b representing, moreover, single bonds oreither of them representing a double bond.

PCT Application WO 93/09094 includes a description of ethers derivedfrom alkyl piperidines or pyrrolidines which are antipsychotic agents,of the formula ##STR5## in which, for the preferred compounds: n and pare 1; and/or m is 1-3; and/or R is phenyl; and/or X is trans --CH═CH--;and/or Ar is phenyl, p-F-phenyl or p-CF₃ -phenyl; and/or the side chainis located at position 4 of the piperidine ring.

Among other dissimilarities, the compounds of PCT applications WO91/03243 and WO 93/09094 differ formally from the compounds of thepresent invention by the existence in their intermediate chain of anoxygen-containing function (C═O, CHOH) or an oxygen atom --O--. It isalso noteworthy that this chain is located, or is declared to bepreferably linked to the carbon atom, at position 4 (para) of thepiperidine ring, and in no case on the carbon atom at position 2,adjacent to the nitrogen atom. These applications do not make mention ofany use of the compounds for the treatment of gastrointestinalcomplaints.

PCT Application WO 92/22527 describes calcium-channel-antagonistcompounds of the formula ##STR6## in which, inter alia: R is (C₁₋₈alkyl) (C₃₋₈ cycloalkyl); p sic! is 0 to 2; n is 0 to 6; A is --CH═CH--;Ar is aryl.

PCT Application WO 93/15052 describes calcium-channel-antagonistcompounds of the formula ##STR7## in which, Ar being optionallysubstituted aryl or heteroaryl, it is defined for the preferredcompounds that: m has the value 0 to 3, R is (C₁₋₈ alkyl) (phenyl)p inwhich p is 0 or 1, or R is (C₂₋₈ alkenyl) (phenyl)p in which p is 1, Ais oxygen or --CH═CH--, the length of the --(CH₂)_(n) A(CH₂)_(m) --chain being from 2 to 6 atoms.

These latter two applications relate to compounds which are calciumchannel antagonists and which differ from the compounds of the presentinvention by virtue of that use. Moreover, contrary to what might beassumed from the declared meanings of R, A, Ar, n and m, none of thecompounds referred to in these documents is prejudicial to the noveltyof the 2-(alkenyl)azacycloalkanes (I) to which the present inventionrelates.

SUMMARY OF THE INVENTION

The invention relates to new 2-(arylalkenyl)azacycloalkane derivativesof the formula ##STR8## in which Ar is aryl or heteroaryl, optionallymono- di- or trisubstituted,

m has the value of 1 or 2,

R is phenyl, optionally substituted, or cycloalkyl containing 3 to 7carbon atoms,

n has the value of 1 to 3,

their isomers, their derivatives in which an atom is replaced by one ofits radioactive isotopes, and their addition salts with thepharmaceutically acceptable acids.

The compounds of the invention show an especially advantageous affinityin vitro for σ receptors, which is indicative of their usefulness in theprevention or treatment of neurological disorders and/or psychoticstates; and, in vivo, they show a pharmacological activity which isespecially indicative of their usefulness in the treatment ofgastrointestinal complaints.

The preferred compounds of the invention are those in which:

Ar is an optionally substituted phenyl radical,

n is 1 or 2,

R is a cyclopropyl, cyclobutyl or phenyl radical.

The present invention also relates to the process for the preparation ofthe azacycloalkanes (I) and to pharmaceutical compositions comprising acompound (I) in combination with pharmaceutically acceptable excipients,diluents or solvents.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an illustration of the reaction scheme for preparing the2-(arylalkyl)azacycloalkane compounds of the present invention; and

FIG. 2 is a diagram of the reaction scheme for the preparation of2-(2-hydroxyethyl)azacycloalkanes from N-nitroso azacycloalkanes.

DETAILED DESCRIPTION OF THE INVENTION

As regards the compounds (I) of the present invention:

Aryl is understood to mean unsaturated mono- or bicycliccarbon-containing radicals such as phenyl, indenyl or naphthyl, whichmay be partially saturated as indanyl or tetrahydronaphthyl. The phenylradical, optionally mono- di- or trisubstituted, is preferred. In thiscase, the substituents, which may be identical or different in the caseof multiple substitution, are selected from the group consisting ofhalogens, the nitro group, and low-molecular-weight alkyl, haloalkyl,alkoxy and haloalkoxy radicals, in which "low-molecular-weight" isunderstood to mean carbon chains comprising 1 to 4 carbon atoms.

Especially preferred is the phenyl radical, unsubstituted, or mono- ordisubstituted by halogen atoms and/or by low-molecular-weight alkoxyradicals such as, preferably, methoxy radicals.

Heteroaryl is understood to mean unsaturated mono- or bicyclic radicalscomprising one or two heteroatoms selected from oxygen, nitrogen andsulfur. Nitrogenous and/or sulfur-containing heterocycles are preferred,especially pyridinyl or thienyl radicals.

As regards isomers, these simultaneously comprise geometrical isomersresulting from the π bond of the arylalkenyl sequence, optical isomersresulting from the asymmetry of the carbon atom at position 2 of theazacycloalkane ring, and mixtures thereof, especially the racemicmixture.

As regards the addition salts of the compounds (I), pharmaceuticallyacceptable acids are understood to mean inorganic or organic acids whichhave been shown to be nontoxic in normal therapeutic doses. These are,as non-restrictive examples, acetic, benzenesulfonic, camphosulfonic,citric, ethanesulfonic, hydrobromic, lactic, maleic, malic,methanesulfonic, mucic, nitric, pamoic, phosphoric, salicylic, stearic,succinic, sulfuric and tartaric acid, and hydrochloric acid, which ispreferred. A review of the salts acceptable in pharmaceutical practicecan be found in J. Pharm. Sci., Vol. 66, 1977, pp. 1-19.

In another aspect, the invention concerns a process for the preparationof the compounds (I), shown in Diagram 1, from an azacycloalkane (III)##STR9## in which n and Ar are as defined for (I), by: either thealkylation of an intermediate (III) with an alkyl halide (IV') ##STR10##in which m and R are as defined for (I) and Y is a halogen, preferablychlorine or bromine,

or, preferably, the acylation of the intermediate (III) with a reactant(IV) ##STR11## in which m and R are as defined for (I) and X is --OH ora halogen such as chlorine or bromine, to furnish an intermediatecarboxamide derivative (II) ##STR12## which is reduced with a metalhydride or an organometallic hydride derived from boron or preferablyfrom aluminum.

More specifically, the process of alkylation of the intermediate (III)with the halide (IV'), which is preferably an alkyl chloride or bromide,is implemented in an inert solvent such as toluene or acetonitrile.Where appropriate, an inorganic basic agent such as sodium carbonate oran organic basic agent such as triethylamine is added to the reactionmedium to promote the reaction. For 1 mol of intermediate (III)introduced, from 0.5 to 1.5 mol of alkyl halide may be used, thereaction being carried out in 2 to 3 liters of the chosen solvent.Depending on the reactants, a satisfactory result is obtained after areaction time of 1 to 24 h at temperatures of 20° to 110° C.

The preferred process of preparation comprises, in a first step, acarboxamide (II) is obtained from the intermediate (III), and then thiscarboxamide is reduced with a metal hydride or an organometallichydride; when X in the reactant (IV) is a halogen such as chlorine orbromine. The reaction is carried out in toluene or preferably methylenechloride, and comprises the addition to a solution containing 1 mol of(III) of 1.0 to 1.5 mol of an organic amine such as triethylamine,followed by the addition of the reactant (IV) in an amount equimolar tothe amine. The solution is then maintained for 3 to 48 h at atemperature of between 0° and 30° C., depending on the nature of thereactants. This reaction scheme is illustrated in FIG. 1.

When X in the reactant (IV) is --OH, a suitable method comprises thepreparation in situ of an anhydride of the acid, optionally mixed,following by the acylation of (III) with this anhydride. The reaction isfavorably carried out in anhydrous apolar solvents of the ether-oxideclass, such as tetrahydrofuran (THF), which is preferred. In an initialphase, the mixed anhydride is prepared at a temperature of between -40°and 0° C. by the addition of 1.0 to 1.5 mol of a tertiary amine such asN-methylmorpholine per mole of acid (IV), followed by 0.9 to 1.2 mole ofisobutyl chloroformiate sic!. One mole of the intermediate (III) is thenadded and the reaction is allowed to proceed for 1 to 48 h at atemperature of between 0° and 60° C. A satisfactory result is generallyobtained after a period of 10 to 20 h with a temperature of between 10°and 25° C.

Alternative methods employ dehydrating agents. These are listed, interalia, in March, J., Advanced Organic Chemistry, 3rd ed., New York:Wiley-Interscience, 1985, p. 372; those comprising the use ofdicyclohexylcarbodiimide or N-N'-carbonyldiimidazole are especiallysuitable.

The second step, which comprises the reduction of the carboxamide (II),involves metal hydrides or organometallic hydrides derived from boron orfrom aluminum. Of these, one may use borane (BH₃) in the form ofcomplexes and, preferably, hydrides derived from aluminum, among whichthere may be cited as examples simple hydrides such as AlH₃ or Dibal(CH₃)₂ --CH--CH₂ !₂ AlH, and mixed hydrides of aluminum and alkalimetals such as sodium or lithium, the preferred reducing agents beinglithium aluminum hydride (LiAlH₄ or LAH) and aluminum hydride AlH₃.

The reactions are carried out in solvents of the ether-oxide class, suchas diethyl ether, 1,2-dimethoxyethane, and, more specifically,tetrahydrofuran (THF), which is especially preferred for reductions withaluminum hydride, which is the method favorably used to reduce thecarboxamides (II). For this purpose, the hydride is prepared in situfrom aluminum halides and metal hydrides, as described, for example, inGaylord, N. J., ed., Reduction with Complex Metal Hydrides,Interscience, 1956, pp. 6-8 and 51-53.

Under the preferred conditions, the reduction in THF of 1 mol ofcarboxamide (II) consists first in generating the aluminum hydride insitu by reacting 0.75 to 2 mol of AlCl₃ with 2.2 to 6 mol of LAH, thesetwo reactants being in a stoichiometric ratio of 1 to 3, and then inreducing (II), which is added at a temperature of between -10° and +30°C. Reaction is maintained for 1 to 24 h at the same temperature; thecomplexes obtained are then decomposed and the compounds of theinvention (I) are isolated by suitable methods customary to a personskilled in the art. Satisfactory results are usually obtained with thesereductions after 2 to 6 h of reaction at a temperature of between 10°and 20° C.

As described, the preparation of the compounds (I) involves the use ofthe essential intermediate azacycloalkanes (III), which are prepared, bymethods described in or adapted from the literature, either from2-(2-hydroxyethyl)azacycloalkanes (VIII) or fromN-nitrosoazacycloalkanes (X), as shown in FIG. 2.

The process for the preparation of the azacycloalkanes (III) from the2-(2-hydroxyethyl)azacycloalkanes (VIII), which are availablecommercially or are prepared according to processes of prior art,comprises, in a first step, the preparation of an intermediate carbamate(VII) in which Z is alkyl, aryl or alternatively polyalkylaryl, thet-butyl radical being, however, preferred in an N-t-butyloxycarbonyl(N-Boc) protective group. The conditions under which these processes ofpreparation are carried out have been amply described, for example byGeiger, R., and Koenig, W., in: Gron, E., and Meienhofer, J., Thepeptides, New York: Academic Press, 1980, Vol. 3, pp. 3-136. Thepreferred agent is di-tert-butyl dicarbonate, which is reacted in slightexcess with compound (VIII), in solution in methylene chloride, at atemperature of between 0° and 30° C.

Controlled oxidation of the carbamate (VII) is then carried out. Thereagent used for this purpose can be selected from among thosedescribed, for example, in March, J., Advanced Organic Chemistry, 3rded., pp. 1057-1060. The preferred reagent is pyridinium chlorochromate,which is used in an ethereal medium or in nitrobenzene, pyridine, oralternatively a halogenated hydrocarbon such as methylene chloride,which is preferred. Commonly, for 1 mole of compound (VII) to beoxidized, from 1.5 to 4 mole of pyridinium chlorochromate are used at atemperature of between 0° and 40° C. for 8 to 30 h in order to obtainthe intermediate aldehyde (VI).

This compound is then subjected to a Wittig reaction with atriphenylphosphonium halide of the formula Ar--CH₂ --P.tbd.(C₆ H₅)₃ ⁺Hal⁻, in which Ar is as defined for (I) and Hal represents a halogensuch as chlorine, bromine or iodine. Different ways of using thereagents are described, as, for example, in Organic Reactions, Vol. 14,p. 270. They involve the use of basic reagents and may be carried out intwo-phase heterogeneous media. The process used consists, however, incarrying out the reaction in an alcohol comprising up to 3 carbon atomsand in the presence of sodium alkoxide, which is formed in situ. Ethanolis preferred, and the triphenylphosphonium derivative and the alkalineagent are present in quantities close to the stoichiometric, thereaction being carried out at a temperature of between 10° and 50° C. toobtain the intermediate N-carbamyl-2-(arylalkenyl)azacycloalkane (V),which is subjected to an N-deprotection reaction, with trifluoroaceticacid, for example, in order to obtain the essential intermediateazacycloalkane (III) in the form of a mixture of Z and E isomers. Theseisomers are separated by conventional techniques, especially bychromatography on a silica column, as well as by selectivecrystallization of the hydrochloride. The Z or E isomers are identifiedby proton NMR, since in --CH_(a) ═CH_(b) -- the coupling constantbetween H_(a) and H_(b) is typically 10 Hz if the molecule is Z andapproximately 17 Hz if it is E (Silverstein, R. M., et al.,Spectrometric Identification of Organic Compounds, 4th edition, NewYork: Wiley, 1981, p. 235).

The alternative process for preparing the compounds (III) should beperformed cautiously, especially in large-volume operations, since itinvolves the use of reactants and intermediates which are hazardous orhave been declared potentially carcinogenic. This process comprises thealkylation of N-nitrosoazacycloalkanes (X), which are commerciallyavailable or are prepared by a nitrosation reaction of azacycloalkane,with an alkylating agent Ar--CH═CH--CH₂ --Hal, in which the halogen ischlorine or bromine, to furnish an intermediateN-nitroso-2-(arylalkenyl)azacycloalkane (IX), which is subjected to anN-denitrosation reaction to furnish the essential intermediate (III).Within the context of the experimental description of the invention,this process is performed on small amounts according to the proceduredescribed by Seebach, D., and Enders, D., Chem. Ber., 1975, Vol. 108,pp. 1293-1320.

An optically active compound (III) may be prepared:

by condensing a racemic compound (III) with an α-amino-acid derivativebelonging to the D series or the L series and in which the aminefunction is protected. After deprotection, the product is separated intoits diastereoisomers by chromatography; Edman degradation then yieldstwo enantiomers of the amine (III); or alternatively,

by dissolving a racemic compound (III) in a solution of optically activeacid, for example an enantiomer of N-actylphenaylalanine, to form twodiastereoisomeric salts, and then, using the difference in solubility,crystallizing out one of the salts selectively in a suitable solvent.

The present invention is illustrated non-restrictively by the examplesthat follow. The state of purity, the physicochemical properties and thestructural identity of the products are determined and reported asfollows:

The products are purified by suitable techniques, especially by columnchromatography, for which the so-called "Chromatoflash" technique on asilica column (supplier: Merck; product: Kieselgel H 60, particle size230 to 400 mesh) is favorably used. The purity of the products isdetermined by thin-layer chromatography (TLC) on silica (Merckready-to-use plates); the Rf values observed and the elution solventsused are indicated in the examples.

The physicochemical properties of the products are represented by:

a) the melting point, determined by the capillary tube method, thestated value being uncorrected;

b) infrared spectrography (IR) of the compounds in KBr disks; the mostintense absorption bands are reported as the value of their wavelengthin cm⁻¹ ;

c) the rotatory power, determined at a temperature in the vicinity of20° C. on a Polartronic apparatus in a cell 10 cm long;

the structural identity of the products is determined on the basis of:

a) proton nuclear magnetic resonance (NMR) determined at 90 or 400 MHz,the products being solubilized in deuterochloroform. The appearance ofthe signals and their chemical shift, expressed in ppm relative totetramethylsilane used as internal reference, are given. Protonscharacterized as exchangeable after the addition of deuterium oxide arealso indicated;

b) elemental percentage analysis, the results of which, in accordancewith the accepted norms, are not reported, but are indicated as havingbeen performed by the listing of the element assayed;

c) high-pressure liquid chromatography on a chiral alpha AGP(α-glycoprotein) column, with UV detection at 220 nm, for assessment ofoptical purity.

EXAMPLES Chemical Experimental Part Preparation 1(E)-(2-cinnamyl)pyrrolidine (formula III; Ar=C₆ H₅, n=1)

Stage a) In a one-liter reactor protected from moisture and in anitrogen atmosphere there are introduced 600 ml of THF dehydrated overmolecular sieve and 25.3 g (35.0 ml-0.25 mol) of diisopropylamine. Thesolution is cooled to -70° C. with a dry ice/acetone mixture, and 100 mlof a 2.5M solution (0.25 mol) of n-butyllithium in hexane are addedwhile the temperature is maintained at -60°/-50° C.

The mixture is kept stirring for 15 minutes at -70° C., and a solutionof 25.0 g (0.25 mol) of N-nitorsopyrrolidine (formula X; n=1) in 25 mlof anhydrous THF is added during 5 min at this same temperature. Theorange solution is stirred for 10 minutes, and 49.3 g (0.25 mol) ofcinnamyl bromide dissolved in 50 ml of anhydrous THF are then addedduring 15 minutes at -70° C.

The reaction medium is maintained for 2 hours at -70° C., and then withstirring for 16 hours at -20°/-25° C., after which 15.0 ml of pureacetic acid are added, causing the formation of some yellowish insolublematter. The suspension is precipitated with stirring in 600 ml ofsaturated NaCl solution and 600 ml of methylene chloride. The aqueousphase is separated and extracted with 200 ml of methylene chloride. Thecombined organic phases are extracted with 200 ml of saturated NaClsolution and are then dehydrated over Na₂ SO₄.

After evaporation of the solvent under vacuum and on a water bath, theresidual brown oil (60.0 g) is purified by chromatography on a silicacolumn. Elution with methylene chloride yields purified(E)-2-cinnamyl-N-nitrosopyrrolidine (formula IX; Ar=C₆ H₅, n=1) in theform of a yellowish viscous oil.

Weight: 24.9 g Yield: 46%

TLC: Rf=0.75-0.85 (50:50 v/v hexane/ethyl acetate)

NMR: 1.80-2.40 (m, 4H); 2.40-3.20 (m, 2H); 3.30-3.90 (m, 2H); 4.25-4.70(m, 1H); 6.00-6.60 (m, 2H); 7.10-7.50 (m, 5H).

Stage b) In a reactor protected from humidity there are introduced 24.0g (0.111 mol) of the N-nitroso derivative obtained in Stage a) above,dissolved in 1200 ml of anhydrous diethylether. With stirring and whilea temperature of 25°±5° C. is maintained, the solution is saturated inthe course of approximately 1 h 30 min by bubbling gaseous hydrochloricacid through it. The solution is left for 16 hours with stirring at15°-20° C., and the excess acid is then removed by bubbling withnitrogen.

The ether phase is extracted with 3×800 ml of water. The combined acidicaqueous phases are alkalinized at a temperature below 10° C. by addingsodium hydroxide solution to pH 12. The mixture is extracted with 3×750ml of ether; the combined ether phases are washed by extractions with3×400 ml of saturated aqueous NaCl solution and are then dried over Na₂SO₄. After evaporation of the ether, the crude product (13.6 g) ispurified by chromatography on a silica column.

Elution with methylene chloride and then with a 92:8 v/v mixture ofmethylene chloride and 10% ammoniacal methanol yields the purifiedcompound in the form of a pale yellow, viscous oil.

Weight: 9.0 g Yield: 43%

TLC: 0.35-0.45 (92:8 v/v methylene chloride/10% ammoniacal methanol)

NMR: 1.20-2.10 (m, 4H); 2.35 (t, 2H); 2.70-3.20 (m, 3H); 3.3 (s, 1Hexch. D₂ O); 6.00-6.60 (m, 2H); 7.00-7.50 (m, 5H).

Stage c) (-)(E)-(2-cinnamyl)pyrrolidine

13.5 g of (±)-(E)-(2-cinnamyl)pyrrolidine obtained in Stage a) above and7.46 g (0.036 mmol) of N-acetyl-L-phenylalanine are dissolved in 250 mlof boiling acetone. After filtration on diatomaceous earth, theinsoluble matter that precipitates upon cooling for 16 h at 20°±3° C. isfiltered out, then recrystallized twice in the same manner.

Treatment in an alkaline medium yields, after extraction with etherfollowed by evaporation, (-)-(E)-(2-cinnamyl)pyrrolidine in the form ofa pale yellow oil.

Weight: 2.5 g α!_(D) =-12.8° (c=1, methylene chloride)

Stage d) (+)-(E)-(2-cinnamyl)pyrrolidine

The filtrate obtained from the first filtration of Stage c) above istreated in an alkaline medium; 9.5 g of a base with a high concentrationof + enantiomer are obtained. As in the preceding stage, adiastereoisomeric salt, this time with N-acetyl-D-phenylalanine, isprepared in acetone. 2.6 g of (+)-E-2-cinnamyl pyrrolidine are obtained.α!_(D) =+13.6° (c=1, methylene chloride)

PREPARATION 2 Intermediates (VI) 1°)N-t-butyloxycarbonyl-2-(2-acetaldehyde)piperidine (formula VI; n=2)

Stage 1: In a two-liter reactor protected from moisture there areintroduced 40.0 g (0.309 mol) of 2-(2-hydroxyethyl)piperidine (formulaVIII; n=2) in 600 ml of methylene chloride dehydrated over molecularsieve. To the pale yellow solution obtained are added rapidly 80.0 g(0.370 mole) of di-tert-butyl dicarbonate. The mixture is left stirringfor one hour at 20°-25° C. and then let stand for 16 h at 20° C.

The solvent is removed by distillation under vacuum and on a water bath.The residual yellow oil is purified by chromatography on a silicacolumn. Elution with a 95:5 v/v mixture of methylene chloride andmethanol furnishes N-t-butyloxycarbonyl-2-(2-hydroxyethyl)piperidine(formula VII; Z=t-butyl, n=2).

Weight: 66.7 g Yield: 94%

TLC: Rf=0.70-0.80 (90:10 v/v ethyl acetate/hexane)

NMR: 1.20-2.20 (m, 18H); 2.50-3.00 (m, 1H); 3.20-3.80 (m, 2H); 3.80-4.50(m, 2H).

Stage 2: In a 3-liter reactor protected from moisture, 66.0 g (0.287mol) of the N-protected alcohol obtained in Stage 1 above are dissolvedin 2.4 liters of anhydrous methylene chloride. 125.0 g (0.58 mol) ofpyridinium chlorochromate are added to the solution. The orangesuspension, which rapidly turns blackish, is maintained at 20°±3° C.,with stirring, for 16 h.

Thereafter, once settling has taken place the organic phase is separatedand is extracted with 1 liter of 1N NaOH solution. The emulsifiedmixture is filtered through a Buchner funnel lined with diatomaceousearth. The filtrate is allowed to settle and the aqueous phase isdecanted and discarded. The organic phase is dehydrated over Na₂ SO₄ andthe solvent is then removed by distillation. The blackish residue (35.0g) is purified by chromatography on a silica column. Elution with ethylacetate yields N-t-butyloxycarbonyl-2-(2-acetaldehyde)piperidine(formula VI; Z=t-butyl, n=2).

Weight: 16.2 g Yield: 25%

TLC: Rf=0.50-0.60 (50:50 v/v methylene chloride/diethyl ether)

NMR: 1.20-2.00 (m, 15H); 2.35-3.00 (m, 3H); 3.80-4.20 (m, 1H); 4.70-5.00(m, 1H); 9.70-9.80 (m, 1H)

2°) N-t-butyloxycarbonyl-2-(2-acetaldehyde)pyrrolidine (formula VI; n=1)

Stage 1:N-Boc-2-pyrrolidine methanol

The compound is prepared as described in § 1°), Stage 1 above, from2-pyrrolidine ethanol, with a yield of 100%.

TLC: Rf=0.70-0.85 (95:15 v/v ethyl acetate/hexane)

Stage 2N-Boc-2-pyrrolidine methanal

The compound is prepared from the N-protected alcohol obtained in Stage1 above, according to the procedure described in § 1°), Stage 2, with ayield of 68%.

TLC: Rf=0.85-0.95 (80:20 v/v ethyl acetate/hexane)

Stage 3:N-Boc-2-(2-methoxyethenyl)pyrrolidine

In a reactor protected from moisture, there are placed 895 ml ofabsolute ethanol, followed, with stirring, by 11.8 g (0.510 mol) ofscraped sodium. After dissolution, at 20°-25° C., 174.7 g of(methoxymethyl)triphenylphosphonium chloride are added. The whitesuspension is stirred for 30 min at 20°-25° C., and a solution of 71 g(0.356 mol) of the aldehyde obtained in Stage 2 above in 199 ml ofabsolute ethanol is then introduced. The reaction medium is kept boilingfor 2 h 30 min and is then cooled and evaporated under vacuum and on awater bath. The orange residue is dissolved in pentane and thenfiltered. The filtrate is concentrated and chromatographed on silica,with elution by means of an 85:15 v/v mixture of hexane and ethylacetate.

Weight=60 g Yield=74%

TLC: Rf=0.75-0.90 (70:30 v/v hexane/ethyl acetate)

Stage 4: In a reactor there are introduced one liter of tetrahydrofuranand 102 g of the vinyl ether obtained in the preceding stage, followedby 150 ml of 10% (w/v) hydrochloric acid. The brown solution is keptstirring at 40° C. for 30 min and then cooled. One liter of ether isadded and, after settling has taken place, the organic phase isseparated, washed with a saturated NaCl solution, and then evaporated.The brown residue is purified by the Chromatoflash technique on silica,with elution by means of a 75:25 v/v mixture of hexane and methylacetate.

Weight: 71.9 g Yield: 75%

Preparation 2A (Z)- and (E)-(2-cinnamyl)piperidine (formula III; Ar=C₆H₅, n=2)

Stage a) In a reactor protected from moisture, there are introduced 180ml of absolute ethanol, followed, with stirring, by 1.63 g (0.071 mol)of scraped sodium. After dissolution, at 20°-25° C., 27.3 g (0.071 mol)of benzyltriphenylphosphonium chloride are added. The yellowishsuspension is kept stirring for 30 min at 20°-25° C. and a solution of16.0 g (0.070 mol) of the previously obtained acetaldehyde (formula VI;n=2) in 35 ml of absolute ethanol is then introduced duringapproximately 2 min. The white solution obtained is maintained for 30minutes at 20°-25° C. and the insoluble matter is filtered out on aBuchner funnel and discarded. The filtrate is evaporated under vacuumand on a water bath. The oily residue is solidified in 500 ml ofn-pentane, and this new insoluble matter is filtered out and removed.The filtrate is concentrated. 19.0 g of crudeN-t-butyloxycarbonyl-(2-cinnamyl)piperidine are obtained (formula V;Z=t-butyl, Ar=C₆ H₅, n=2) (yield=90%) and are introduced in the nextstage without further treatment.

Stage b) In a reactor protected from moisture, 19.0 g (0.063 mol) of thecompound (V) obtained in the preceding stage are dissolved in 400 ml ofanhydrous methylene chloride. The solution is cooled with an ice bath,and 190 ml of pure trifluoroacetic acid are added with stirring over aperiod of 10 minutes at a temperature below 5° C. The solution ismaintained at this temperature for 30 minutes and is then concentratedunder vacuum and on a water bath. The residue is dissolved in 600 ml ofether and extracted with 200 ml of 1N NaOH solution. The ether phase iswashed with water and then dried over Na₂ SO₄.

The ether is evaporated and the crude product (12.0 g) is obtained inthe form of a light brown oil, which is dissolved in 120 ml of anhydrousmethylene chloride. To this solution are added 25 ml of 5N etherealhydrogen chloride and the solvents are then evaporated by distillation.The residue is dissolved in 150 ml of boiling isopropanol. The insolublematter which precipitates on cooling with stirring is filtered out on aBuchner and then recrystallized in absolute ethanol. After removal ofthe residual solvents under vacuum, (E)-(2-cinnamyl)piperidinehydrochloride is obtained (formula III-E; Ar=C₆ H₅, n=2).

Weight: 4.6 g Yield: 30.7% mp: 225° C.

TLC: Rf=0.30-0.40 (90:10 v/v methylene chloride/10% ammoniacal methanol)

Analysis (C₁₄ H₂₀ ClN): % C, H, Cl, N in agreement.

Treatment of 4.0 g (16.8 mmol) of the hydrochloride in an alkalinemedium and extraction with ether followed by evaporation yields 3.3 g of(E)-(2-cinnamyl)piperidine in the form of a pale yellow, viscous oil.

NMR: 1.00-1.90 (m, 6H); 1.95 (s, 1H exch. D₂ O); 2.10-2.40 (m, 2H);2.40-2.80 (m, 2H); 2.90-3.20 (m, 1H); 6.00-6.60 (m, 2H); 7.10-7.45 (m,5H).

The previously obtained isopropanol-containing filtrate is concentratedby distillation. The residue (9.0 g) is treated and extracted in analkaline medium with ether. The ether is removed and the oily residue(6.4 g) purified by chromatography on a silica column. Elution with a95:5 v/v mixture of methylene chloride and 10% ammoniacal methanolyields pure (Z)-(2-cinnamyl)piperidine (formula III-Z; Ar=C₆ H₅, n=2) inthe form of a highly viscous oil which solidifies slowly in the coldstate.

Weight: 3.0 g Yield: 23.7%

TLC: Rf=0.40-0.50 (90:10 v/v methylene chloride/10% ammoniacal methanol)

NMR: 1.00-1.90 (m, 6H); 2.20 (s, 1H exch. D₂ O); 2.30-2.80 (m, 4H);2.90-3.20 (m, 1H); 5.50-5.85 (m, 1H); 6.40-6.60 (m, 1H); 7.10-7.40 (m,5H);

Stage c) (-)-(E) -(2-cinnamyl)piperidine.

From (±)-(E)-(2-cinnamyl)piperidine obtained in the preceding stage,according to a method similar to that of Preparation 1, Stage c), inwhich the last recrystallization is carried out in an aqueous medium,there is obtained (-)-(E)-(2-cinnamyl)piperidine in the form of an oil,with a yield of 33%. α!_(D) =-8.10 (c=2, methylene chloride)

Stage d) (+)-(E) -(2-cinnamyl)piperidine.

According to the process described for Preparation 1, Stage d), the lastrecrystallization being performed in an aqueous medium,(+)-(E)-(2-cinnamyl)piperidine is obtained with a yield of 30% afterreturn to the base. α!_(D) =+8.10 (c=2, methylene chloride)

Preparation 2B (Z)- and (E)-2-(p-fluorocinnamyl)piperidine (formula III;Ar=p-fluorophenyl, n=2)

Stage a) According to the method of Preparation 2A, Stage a), fromp-fluorobenzyl triphenylphosphonium there is obtainedN-t-butyloxycarbonyl-2-(p-fluorocinnamyl)piperidine in the form of ayellow oil with a yield of 96%.

Stage b) Deprotection with trifluoroacetic acid is performed accordingto the method of Preparation 2A, Stage b). The crude product obtained inthe form of an orangish-yellow oil is a mixture of the Z and E isomerswhich is separated by the Chromatoflash technique on a silica column.Elution with a mixture of methylene chloride and 10% ammoniacal methanolin a v/v ratio of 95:5, followed by 90:10, furnishes different fractionsin succession. To the least polar fractions, dissolved in methylenechloride, is added 5N ethereal hydrogen chloride; the solvents are thenevaporated and the residue is dissolved in isopropanol and solidified,with stirring, by the addition of ether. A white precipitate of(Z)-2-(p-fluorocinnamyl)piperidine hydrochloride is obtained. mp=135° C.

Treatment in an alkaline medium, extraction with ether and evaporationfurnishes (Z)-2-(p-fluorocinnamyl)piperidine in the form of a yellowoil.

Yield: 13%

TLC: Rf=0.70-0.85 (80:20 v/v methylene chloride/10% ammoniacal methanol)

Comparable treatment of the most polar fractions yields(E)-2-(p-fluorocinnamyl)piperidine in the form of a white precipitate.

mp=193° C. (isopropanol)

Return to the base furnishes (E)-2-(p-fluorocinnamyl)piperidine with ayield of 25%.

TLC: RF=0.60-0.75 (80:20 v/v methylene chloride/10% ammoniacal methanol)

Preparation 2C (E)-2-(p-chlorocinnamyl)piperidine (formula III;Ar=p-chlorophenyl, n=2)

Stage a) According to the method of Preparation 2A, Stage a), fromp-chlorobenzyl triphenylphosponium, there is obtainedN-t-butyloxycarbonyl-2-(p-chlorocinnamyl)piperidine in the form of ayellow oil with a yield of 94%.

Stage b) Deprotection with trifluoroacetic acid is performed accordingto the method of Preparation 2A, Stage b). The product, obtained in theform of a yellow oil, is a mixture of the Z and E isomers. Elution witha 90:10 v/v mixture of methylene chloride and 10% methanol by theChromatoflash technique on silica furnishes(E)-2-(p-chlorocinnamyl)piperidine in the form of a pale yellow oil witha yield of 24%.

Preparation 2D (E)-2-(m-chlorocinnamyl)piperidine (formula III;Ar=p-chlorophenyl, n=2)

Stage a) According to a method similar to that of Preparation 2A, Stagea), from m-chlorobenzyl triphenylphosponium there is obtainedN-t-butyloxycarbonyl-2-(m-chlorocinnamyl)piperidine with a yield of 99%.

Stage b) Deprotection with trifluoroacetic acid is carried out accordingto the method of Preparation 2A, Stage b). The product obtained is amixture of the Z and E isomers. Elution with a 90:10 v/v mixture ofmethylene chloride and 10% ammoniacal methanol by the Chromatoflashtechnique on silica furnishes the E isomer in the most polar fractions.The intermediate fractions are chromatographed a second time under thesame conditions. All of the fractions with a high E-isomer content arecombined, and, as described with regard to Preparation 2B, Stage b), areconverted to the hydrochloride, which is recrystallized in isopropanol,then treated in an alkaline medium, extracted with ether andconcentrated to furnish (E)-2-(m-chlorocinnamyl)piperidine with a yieldof 24%.

Preparation 2E (E)-2-(3,4-dichloro)cinnamyl piperidine (formula III;Ar=3,4-dichlorophenyl, n=2)

Stage a) According to Method 2A, Stage a), from 3,4-dichlorobenzyltriphenylphosphonium chloride there is obtainedN-t-butyloxycarbonyl-2-(3,4-dichloro)cinnamyl piperidine in the form ofa yellow oil. Yield: 91%.

TLC: Rf=0.60-0.80 (methylene chloride)

Stage b) Deprotection with trifluoroacetic acid and separation of the Eisomer are performed according to the method described for Stage b) ofPreparation 2D. (E)-2-(3,4-dichloro)cinnamyl piperidine is obtained inthe form of a yellow oil with a yield of 18%.

TLC: Rf=0.35-0.55 (90:10 v/v methylene chloride/10% ammoniacal MeOH)

Preparation 2F (E)-2-(p-methylcinnamyl)piperidine (formula III;Ar=p-toluyl, n=2)

Stage a) According to Method 2A, Stage a), from p-methylbenzyltriphenylphosphonium, there is obtainedN-t-butyloxycarbonyl-2-(p-methylcinnamyl)piperidine (f. V; Ar=p-toluyl,n=2) in the form of an orangish-yellow oil. Yield: 98%

TLC: Rf=0.25-0.55 (methylene chloride)

Stage b) The intermediate V from the preceding stage is deprotected andthe E isomer is separated according to the method of Preparation 2D,Stage b). (E)-2-(p-methylcinnamyl)piperidine is obtained in the form ofa yellow oil with a yield of 14%. The corresponding hydrochloride is awhite solid with a melting point of 178° C. (isopropanol).

Preparation 2G (E)-2-(p-trifluoromethylcinnamyl)piperidine (formula III;Ar=p-trifluoromethylphenyl, n=2)

Stage a) According to Method 2A, Stage a), fromp-trifluoromethylbenzyltriphenyl phosphonium there is obtainedN-Boc-2-(p-trifluoromethylcinnamyl)piperidine (formula V;Ar=p-trifluoromethylphenyl, n=2) in the form of a yellow oil.

Yield: 94%

Stage b) The intermediate V from the preceding stage is deprotected andthe E isomer is separated according to the method of Preparation 2B,Stage b), applied to the E isomer.(E)-2-(p-trifluoromethylcinnamyl)piperidine is obtained with a yield of17%.

Preparation 2H (E)-2-(p-methoxycinnamyl)piperidine (formula III;Ar=p-methoxyphenyl, n=2)

Stage a) According to Process 2A, Stage a), fromp-methoxybenzyltriphenyl phosphonium chloride,N-Boc-2-(p-methoxycinnamyl)piperidine (formula V; Ar=p-methoxyphenyl,n=2) is obtained in the form of a yellow oil and is purified bychromatography on a silica column, with elution by means of a 98:2 v/vmixture of methylene chloride and acetone. Yield: 94%.

TLC: Rf=0.55-0.75 (98:2 v/v methylene chloride/acetone)

Stage b) Intermediate V from the preceding stage is deprotected and theE isomer is purified according to Process 2D, Stage b).(E)-2-(p-methoxycinnamyl)piperidine is obtained in the form of a yellowoil with a yield of 15%.

TLC: Rf=0.45-0.70 (90:10 v/v methylene chloride/10% ammoniacal MeOH).

Preparation 2I (E)-2-(1-naphth-1-yl-propen-3-yl)piperidine (formula III;Ar=naphth-1-yl, n=2)

Stage a) According to Process 2A, Stage a), fromnaphth-1-yl-methyltriphenyl phosponium there is obtainedN-Boc-2-(1-naphth-1-yl-propen-3-yl)piperidine (formula V;Ar=naphth-1-yl, n=2) with a yield of 79%.

Stage b) Intermediate V from the preceding stage is deprotected and theE isomer is separated according to a method similar to that ofPreparation 2B, Stage b). (E)-2-(1-naphth-1-yl-propen-3-yl)piperidine isobtained with a yield of 19%.

Preparation 2J (E) -2-(1-thien-2-yl-propen-3-yl)piperidine (formula III;Ar=thien-2-yl, n=2)

Stage a) According to a method similar to that of Preparation 2A, Stagea), from thien-2-yl-methyltriphenyl phosponium chloride there isobtained N-Boc-2-(1-thien-2-yl-propen-3-yl) piperidine with a yield of91%.

Stage b) Deprotection is carried out according to Process 2B, Stage b).(E)-2-(1-thien-2-yl-propen-3-yl)piperidine is obtained with a yield of5%.

Preparation 2K (Z)-2-(cinnamyl)pyrrolidine (formula III-Z; Ar=C₆ H₅,n=1)

Stage a) In a reactor protected from moisture, there are introduced 235ml of absolute ethanol, followed, with stirring, by 2.16 g (0.094 mol)of scraped sodium. After dissolution, at 20°-25° C., 36.5 g (0.094 mol)of benzyltriphenyl phosphonium chloride are added. The yellow solutionis kept stirring for 30 min, after which a solution of 20 g (0.094 mol)of the previously obtained acetaldehyde (formula VI; n=1) in 47 ml ofabsolute ethanol is introduced during approximately 2 min. The whitesuspension is kept stirring for 45 min at 20°-25° C., and the insolublematter is then filtered out on a Buchner and discarded. The filtrate isevaporated under vacuum and on a water bath. The oily residue, dissolvedin 300 ml of pentane, is maintained at 0° C. for 2 h with stirring, andis then filtered and concentrated. This last step is repeated. Theproduct is 24.5 g (yield=91%) of crude N-Boc-2-(cinnamyl)pyrrolidine(formula V; Ar=C₆ H₅, n=1) in the form of a yellow oil, which isintroduced in the next stage without further treatment.

Stage b) The intermediate V from the preceding stage is deprotected andthe Z isomer is separated according to a method similar to that ofPreparation 2D, Stage b). (Z)-2-(cinnamyl)pyrrolidine is obtained with ayield of 28%.

TLC: Rf=0.35-0.50 (90:10 v/v methylene chloride/10% ammoniacal MeOH)

Preparation 2L (E)-2-(p-fluorocinnamyl)pyrrolidine (formula III;Ar=p-fluorophenyl, n=1)

Stage a) In a reactor protected from moisture there are introduced 42 g(0.103 mol) of p-fluorobenzyltriphenyl phosphonium chloride in 235 ml oftoluene dehydrated on molecular sieve. 60 ml of a 2.5M solution ofn-butyllithium in hexane are then introduced during 10 min. The redsuspension is kept stirring for 2 h at 20°-25° C., after which 20 g(0.094 mol) of the previously obtained acetaldehyde (formula VI; n=1) in42.2 ml of toluene are introduced. The dark red suspension obtained iskept stirring for 16 h, after which 80 ml of a saturated ammoniumchloride solution are introduced with cooling to 20° C. After 15 min ofstirring, the insoluble matter is filtered out and discarded. Aftersettling has taken place, the toluene phase of the filtrate isseparated, dried over Na₂ SO₄ and evaporated. The oily brown residue issolidified in 300 ml of n-pentane, and the new insoluble matter isfiltered out and removed; the filtrate is concentrated. This lastpurification step is repeated. 23.6 g (yield: 82%) of crudeN-Boc-2-(p-fluorocinnamyl)pyrrolidine are obtained (formula V;Ar=p-fluorophenyl, n=1) in the form of an orange oil.

Stage b) Deprotection with trifluoroacetic acid and separation of the Eisomer are carried out according to the method of Preparation 2B, Stageb) applied to the E isomer, with recrystallization in ethyl acetate.(E)-2-(p-fluorocinnamyl)pyrrolidine hydrochloride is obtained in theform of a white precipitate. Return to the base furnishes(E)-2-(p-fluorocinnamyl)pyrrolidine with a yield of 19%.

TLC: Rf=0.30-0.50 (90:10 v/v methylene chloride/10% ammoniacal MeOH)

Example 1.1 (±)-(E)-2-cinnamyl-1-cyclopropylmethylpyrrolidine (formulaI; Ar=C₆ H₅, m=1, n=1, R=cyclopropyl)

Stage a) In a reactor protected from moisture, there are introduced 4.5g (0.024 mol) of (E)-2-(cinnamyl)pyrrolidine (Preparation 1, Stage b)dissolved in 100 ml of methylene chloride dehydrated over molecularsieve. 2.5 g (3.5 ml-0.025 mol) of triethylamine are added withstirring, followed by 2.5 g (2.2 ml-0.024 mol) of cyclopropanecarboxylicacid chloride (formula IV; m=1, R=cyclopropyl) at a temperature below10° C. during approximately 10 min. The brown solution is kept stirringfor 1 h and the mixture is extracted successively with:

30 ml of 10% ammonia solution followed by 30 ml of water,

30 ml of 10% HCl solution followed by 30 ml of water,

30 ml of saturated NaHCO₃ solution followed by 30 ml of water.

The organic phase is dehydrated over Na₂ SO₄ and the solvent is thenevaporated under vacuum and on a water bath. The oily residue (5.9 g) ispurified by chromatography on a silica column. Elution with a 95:5 v/vmixture of methylene chloride and acetone yields pure2-cinnamyl-1-cyclopropanecarbonylpyrrolidine (formula II; Ar=C₆ H₅, m=1,n=1, R=cyclopropyl) in the form of a yellow oil.

Weight: 4.2 g Yield: 65.8%

TLC: Rf=0.35-0.45 (95:5 v/v methylene chloride/acetone)

NMR: 0.60-1.20 (m, 4H); 1.40-2.05 (m, 5H); 2.10-2.90 (m, 2H); 3.40-3.75(m, 2H); 4.00-4.35 (m, 1H); 5.85-6.60 (m, 2H); 7.10-7.50 (m, 5H).

Stage b) In a nitrogen atmosphere, under protection from moisture andwithout exceeding 0° C., there are prepared, on the one hand, asuspension of 1.9 g (0.049 mol) of lithium aluminum hydride (LAH) in 25ml of THF dehydrated on molecular sieve, and on the other hand, asolution of 2.15 g (0.016 mol) of aluminum chloride in 25 ml of diethylether, also dehydrated on sieve.

After 30 min of contact for each preparation, the LAH/THF suspension isadded to the ethereal AlCl₃ solution during 10 min at 0° C., and asolution of 4.0 g (0.016 mol) of the amide (II) obtained in thepreceding stage in 16 ml of anhydrous THF is then added at thistemperature and during 10 minutes. After 30 minutes at 0° C., themixture is brought to reflux for 10 min and is then cooled rapidly to 0°C. There are then added, dropwise and cautiously, 2.9 ml of 15% (w/v)NaOH solution followed by 3.6 ml of water. After 30 minutes of contact,the mixture is filtered through a Buchner funnel lined with a bed ofdiatomaceous earth. The filtrate is concentrated under vacuum and on awater bath to yield (E)-2-cinnamyl-N-cyclopropylmethylpyrrolidine, whichis shown to be pure by TLC.

Weight: 3.2 g Yield: 84.6%

TLC: Rf=0.55-0.75 (95:5 v/v methylene chloride/acetone)

NMR: 0.00-0.30 (m, 2H); 0.40-0.70 (m, 2H); 0.80-1.20 (m, 1H); 1.40-3.00(m, 10H); 3.20-3.50 (m, 1H); 6.00-6.60 (m, 2H); 7.10-7.55 (m, 5H).

Hydrochloride: The base is dissolved in 50 ml of methylene chloride, 5ml of 5N ethereal hydrogen chloride are added and the solvents areremoved by distillation. The solid residue is crystallized bydissolution in 50 ml of ethyl acetate. The white insoluble matter isfiltered out and dried under vacuum to constant weight. mp=163° C.

Analysis (C₁₇ H₂₄ ClN): % C, H, Cl, N in agreement

IR (KBr): 2950, 2500, 1460, 1440, 1050, 1020, 970, 940, 830, 740, 690cm⁻¹.

Example 1.2 (+)-(E)-2-cinnamyl-1-cyclopropylmethylpyrrolidine (formulaI; Ar=C₆ H₅, m=1, n=1, R=cyclopropyl)

The compound is prepared as described in Example 1.1 above, from(-)-(E)-2-(cinnamyl)pyrrolidine (Preparation 1, Stage c).

Stage a) (+)-(E)-2-cinnamyl-1-cyclopropanecarbonylpyrrolidine (f. II;Ar=C₆ H₅, m=1, n=1, R=cyclopropyl) Yield: 100% α!_(D) =24.5° (c=1,methylene chloride)

TLC: Rf=0.35-0.50 (95:5 v/v methylene chloride/acetone)

Stage b) (+)-(E)-2-cinnamyl-1-cyclopropylmethylpyrrolidine

Yield: 96% α!D=91.9° (c=1, methylene chloride)

TLC: Rf=0.45-0.60 (95:5 v/v methylene chloride/10% ammoniacal MeOH)

NMR: Same as for the racemic compound (Ex. 1.1).

Hydrochloride: mp=196°-198° C. (isopropanol).

Analysis (C₁₇ H₂₁ ClN): % C, H, N in agreement.

IR (KBr): Same as for the racemic compound (Ex. 1.1).

Example 1.3 (-)-(E)-2-cinnamyl-1-cyclopropylmethylpyrrolidine (formulaI; Ar=C₆ H₅, m=1, n=1, R=cyclopropyl)

The compound is prepared as described in Example 1.1 above, from (+)-(E)-2-(cinnamyl)pyrrolidine (Preparation 1, Stage d).

Stage a) (-)-(E)-2-cinnamyl-1-cyclopropanecarbonylpyrrolidine (formulaII; Ar=C₆ H₅, m=1, n=1, R=cyclopropyl)

Yield: 100% α!_(D) =-20.80 (c=1, methylene chloride)

TLC: Rf=0.35-0.50 (95:5 v/v methylene chloride/acetone)

Stage b) (-)-(E)-2-cinnamyl-1-cyclopropylmethylpyrrolidine Yield: 94%α!_(D) =+91.8° (c=1, methylene chloride)

TLC: Rf=0.45-0.60 (95:5 v/v methylene chloride/10% ammoniacal MeOH)

NMR: Same as for the racemic compound (Ex. 1.1).

Hydrochloride: mp=196°-198° C. (isopropanol).

Analysis (C₁₇ H₂₄ ClN): % C, H, N in agreement.

IR: Same as for the racemic compound (Ex. 1.1).

Example 1.4 (E)-2-cinnamyl-1-cyclobutylmethylpyrrolidine (formula I;Ar=C₆ H₅, m=1, n=1, R=cyclobutyl)

Stage a) According to the method of Example 1.1, Stage a), from2-(cinnamyl)pyrrolidine and cyclobutanecarboxylic acid chloride there isobtained, with a yield of 95%,2-cinnamyl-1-cyclobutanecarbonylpyrrolidine (formula II; Ar=C₆ H₅, m=1,n=1, R=cyclobutyl), which is introduced in the next stage withoutfurther treatment.

Stage b) Reduction performed according to the method of Example 1.1,Stage b), with LAH-AlCl₃, results in2-cinnamyl-1-cyclobutylmethylpyrrolidine with a yield of 45%.

TLC: Rf=0.50-0.60 (95:5 v/v methylene chloride/10% ammoniacal MeOH)

NMR: 1.40-3.20 (m, 18H); 5.95-6.95 (m, 2H); 7.00-7.45 (m, 5H).

Hydrochloride: The compound, prepared as described in Example 1.1, iscrystallized in a methylene chloride/ethyl ether mixture. mp=170°-171°C.

Analysis (C₁₈ H₂₆ ClN): % C, H, Cl, N in agreement.

IR (KBr): 2950, 2500, 1440, 1240, 1020, 970, 740, 680 cm⁻¹.

Example 1.5 (E)-2-cinnamyl-1-cyclopropylethylpyrrolidine (formula I;Ar=C₆ H₅, m=2, n=1, R=cyclopropyl)

Stage a) In a reactor protected against moisture, there are introduced 1g (0.010 mol) of cyclopropaneacetic acid, 2.34 g (0.012 mol) of(E)-2-(cinnamyl)pyrrolidine dissolved in 80 ml of methylene chloridedehydrated over molecular sieve and 2.9 g (0.015 mol) of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. The brownsolution is kept stirring for 16 h at 20°-25° C. and the mixture isextracted successively with:

50 ml of 1N HCl solution followed by 2×50 ml of water,

50 ml of saturated NaHCO₃ solution followed by 2×50 ml of water.

The organic phase is dehydrated over Na₂ SO₄ and filtered, and thesolvent is then evaporated under vacuum and on a water bath.

2-cinnamyl-1-cyclopropaneacetylpyrrolidine (formula II; Ar=C₆ H₅, m=2,n=1, R=cyclopropyl) is obtained in the form of a brown oil. Weight=2.2 gYield=82%

TLC: Rf=0.85-0.95 (92:8 v/v methylene chloride/10% ammoniacal MeOH)

Stage b) Amide II from the preceding stage is reduced according to themethod described in Example 1.1, Stage b), followed by a purificationstep by chromatography on a silica column. Elution with a 90:10 v/vmixture of methylene chloride and 10% ammoniacal methanol mixture yields(E)-2-cinnamyl-1-(cyclopropylethyl)pyrrolidine in the form of a yellowoil.

Weight: 1.7 g Yield: 81%

TLC: Rf=0.85-1.00 (90:10 v/v methylene chloride/10% ammoniacal MeOH)

NMR: 0-0.10 (m, 2H); 0.40-0.50 (m, 2H); 0.70-0.80 (m, 1H); 1.30-1.90 (m,7H); 2.10-2.30 (m, 2H); 2.30-2.40 (m, 1H); 2.50-2.60 (m, 1H); 2.90-3.00(m, 1H); 3.10-3.20 (m, 1H); 6.10-6.20 (m, 1H); 6.45 (d, 1H); 7.10-7.40(m, 5H)

Hydrochloride: mp=188° C. (isopropanol)

Analysis (C₁₈ H₂₆ ClN): % C, H, Cl, N in agreement.

IR: 2900, 2400, 1420, 1020, 960, 900, 740, 700 cm⁻¹.

Example 1.6 (E)-2-cinnamyl-1-phenethylpyrrolidine (formula I; Ar=C₆ H₅,m=2, n=1, R=C₆ H₅)

Stage a) The procedure is the same as that of Example 1.1, Stage a), theinitial reactants being (E)-2-cinnamylpyrrolidine and phenylacetic acidchloride. (E)-2-cinnamyl-1-phenylacetylpyrrolidine is obtained with ayield of 97% and is introduced in the next stage without furthertreatment.

Stage b) Reduction according to the method of Example 1.5, Stage b)furnishes (E)-2-cinnamyl-1-(phenethyl)pyrrolidine with a yield of 45%.

TLC: Rf=0.80-0.95 (90:10 v/v methylene chloride/10% ammoniacal MeOH)

NMR: 1.50-2.00 (m, 4H); 2.10-2.30 (m, 2H); 2.30-2.60 (m, 3H); 2.70-2.90(m, 2H); 3.00-3.20 (m, 1H);

3.20-3.30 (m, 1H); 6.10-6.20 (m, 1H); 6.45 (d, 1H); 7.10-7.40 (m, 10H).

Hydrochloride: (mp=120°-122° C. (ethyl acetate/ethyl ether).

Analysis (C₂₁ H₂₆ ClN): % C, H, Cl, N in agreement.

IR (KBr): 2900; 2450; 1600; 1490; 1450; 1050; 990; 740; 690 cm⁻¹.

Example 2A.1 (E)-2-cinnamyl-1-cyclopropylmethylpiperidine (formula I;Ar=C₆ H₅, m=1, n=2, R=cyclopropyl).

Stage a) The method is the same as that of Example 1.1, Stage a), theinitial reactants being (E)-2-(cinnamyl)piperidine (Preparation 2A,Stage b) and cyclopropanecarboxylic acid chloride, yielding(E)-2-cinnamyl-1-cyclopropanecarbonylpiperidine (formula II; Ar=C₆ H₅,m=1, n=2, R=cyclopropyl). Yield: 95%.

TLC: Rf=0.80-0.90 (ethyl acetate)

NMR: 0.50-1.10 (m, 5H); 1.30-1.90 (m, 8H); 4.00-5.00 (m, 1H); 5.90-0.60(m, 2H); 7.10-7.40 (m, 5H).

Stage b) Amide (II) from the preceding stage is reduced as described inExample 1.1, Stage b) to yield (E)-2-cinnamyl-1-cyclopropane carbonylpiperidine. Yield: 86%

TLC: Rf=0.65-0.80 (95:5 v/v methylene chloride/10% ammoniacal MeOH)

NMR: 0.10-0.20 (m, 2H); 0.20-0.60 (m, 2H); 0.60-1.00 (m, 1H); 1.10-1.80(m, 6H); 2.10-2.80 (m, 6H); 2.60-3.20 (m, 1H); 5.95-6.55 (m, 2H);7.10-7.40 (m, 5H).

Hydrochloride: The compound is prepared under the conditions describedin Example 1.1, the crystallization being carried out in boiling ethylacetate. mp=152° C.

Analysis (C₁₈ H₂₆ ClN): % C, H, Cl, N in agreement;

IR(KBr): 2950, 2680, 2500, 1440, 1360, 1260, 1200, 1120, 1020, 980, 980,950, 820, 800, 770, 740, 680 cm⁻¹.

Example 2A.2 (+)-(E)-2-cinnamyl-1-(cyclopropylmethyl)piperidine (formulaI; Ar=C₆ H₅, m=1, n=2, R=cyclopropyl)

The compound is prepared as described in Example 2A.1 above, from(-)-(E)-2-(cinnamyl)piperidine (Preparation 2A, Stage c).

Stage a) (-)-(E)-2-cinnamyl-1-(cyclopropane)carbonylpiperidine (formulaII; Ar=C₆ H₅, m=1, n=2, R=cyclopropyl)

Yield: 100% α!_(D) =-6.40 (c=4, methylene chloride)

TLC: Rf=0.60-0.75 (95:5 v/v methylene chloride/acetone)

Stage b) (+)-(E)-2-cinnamyl-1-(cyclopropylmethyl)piperidine

Yield: 95% α!_(D) =+27.70 (c=1, methylene chloride)

TLC: 0.60-0.75 (95:5 v/v methylene chloride/acetone)

NMR: Same as for the racemic compound (Ex. 2A.1)

Hydrochloride: mp=153° C. (ethyl acetate).

Analysis (C₁₈ H₂₆ ClN): % C, H, Cl, N in agreement;

IR (KBr): Same as for the racemic compound (Ex. 2A.1)

Example 2A.3 (-)-(E)-2-(cinnamyl)cyclopropylmethylpiperidine (formula I;Ar=C₆ HS, m=1, n=2, R=cyclopropyl)

The compound is prepared as described in Example 2A.1 above, from(+)-(E) -2- (cinnamyl)piperidine (Preparation 2A, Stage d).

Stage a) (+)-(E)-2-cinnamyl-1-(cyclopropane)carbonylpiperidine (formulaII; Ar=C₆ H₅, m=1, n=2, R=cyclopropyl)

Yield: 100% a!=+6.30 (c=4.5, methylene chloride)

TLC: Rf=0.60-0.75 (95:5 v/v methylene chloride/acetone)

Stage b) (-)-(E)-2-cinnamyl-1-(cyclopropylmethyl)piperidine

Yield: 94% α!_(D) =-28.5° (c=1, methylene chloride)

TLC: Rf=0.45-0.65 (95:5 v/v methylene chloride/10% ammoniacal MeOH)

NMR: Same as for the racemic compound (Ex. 2A.1).

Hydrochloride: mp=151°-152° C. (ethyl ether/isopropanol).

Analysis (C₁₈ H₂₆ ClN): % C, H, Cl, N in agreement.

IR: Same as for the racemic compound (Ex. 2A.1).

Example 2A.4 (E) -2-cinnamyl-1-cyclobutylmethylpiperidine (formula I;Ar=C₆ H₅, m=1, n=2, R=cyclobutyl)

Stage a) The method is the same as that of Example 1.1, Stage a), theinitial reactants being (E)-2-(cinnamyl)piperidine andcyclobutanecarboxylic acid chloride, which furnish(E)-2-cinnamyl-1-(cyclobutanecarbonyl)piperidine (formula II; Ar=C₆ H₅,m=1, n=2, R=cyclobutyl). Yield: 99%.

TLC: Rf=0.40-0.55 (95:5 v/v methylene chloride/acetone)

Stage b) The intermediate from the preceding stage is reduced under theconditions described in Example 1.1, Stage b) to furnish(E)-2-cinnamyl-1-(cyclobutanecarbonyl)piperidine. Yield: 86%.

TLC: Rf=0.65-0.90 (95:5 v/v methylene chloride/10% ammoniacal MeOH)

NMR: 1.0-2.60 (m, 18H); 2.70-2.80 (m, 2H); 6.10-6.20 (m, 1H); 6.40 (d,1H); 7.10-7.40 (m, 5H).

Hydrochloride: mp=163° C. (ethyl acetate).

Analysis (C₁₉ H₂₈ ClN): % C, H, Cl, N in agreement;

IR (KBr): 2900, 2500, 1440, 1210, 1080, 980, 860, 700 cm⁻¹.

Example 2A.5 (E)-2-cinnamyl-1-(phenethyl)piperidine (formula I; Ar=C₆H₅, m=2, n=2, R=C₆ H₅)

The compound is prepared as described in Example 1.6 above from(E)-2-(cinnamyl)piperidine and phenylacetic acid chloride.

Stage a) (E)-2-cinnamyl-1-(phenylacetyl)piperidine (formula II; Ar=C₆H₅, m=2, n=2, R=C₆ H₅) Yield: 99%

TLC: Rf=0.50-0.60 (95:5 v/v methylene chloride/acetone)

Stage b) (E)-2-cinnamyl-1-(phenethyl)piperidine Yield: 73%

TLC: Rf=0.60-0.80 (98:2 v/v methylene chloride/10% ammoniacal MeOH)

NMR: 1.30-1.80 (m, 6H); 2.30-2.60 (m, 4H); 2.80-3.00 (m, 5H); 6.10-6.20(m, 1H); 6.40 (d, 1H); 7.10-7.40 (m, 10H)

Hydrochloride: Hygroscopic compound, m.p.=95°-100° C. (ethylether/isopropanol)

Analysis (C₂₂ H₂₈ ClN): % C, H, Cl, N in agreement;

IR (KBr): 3400, 2900, 2500, 1600, 1430, 1260, 1080, 740, 690 cm⁻¹.

Example 2A.6 (Z)-2-cinnamyl-1-cyclopropylmethylpiperidine (formula I;Ar=C₆ H₅, m=1, n=2, R=cyclopropyl)

The compound is prepared as described in Example 2A.1 above from(Z)-2-(cinnamyl)piperidine (Preparation 2A, Stage b).

Stage a) (Z)-2-cinnamyl-1-(cyclopropane)carbonylpiperidine (formula II;Ar=C₆ H₅, m=1, n=2, R=cyclopropyl) Yield: 96%

TLC: Rf=0.75-0.80 (ethyl acetate)

NMR: 0.60-0.85 (m, 2H); 0.85-1.10 (m, 2H); 1.10-1.90 (m, 9H); 2.40-3.00(m, 2H); 3.80-5.00 (m, 1H); 5.45-5.85 (m, 1H); 6.40-6.70 (m, 1H);7.10-7.50 (m, 5H).

Stage b) (Z)-2-cinnamyl-1-cyclopropylmethylpiperidine.

Yield: 91.2%

TLC: Rf=0.50-0.70 (95:5 v/v methylene chloride/10% ammoniacal MeOH)

NMR: 0.00-0.10 (m, 2H); 0.30-0.60 (m, 2H); 0.60-1.00 (m, 1H); 1.10-1.80(m, 6H); 2.00-2.65 (m, 6H); 2.90-3.20 (m, 1H); 5.45-5.90 (m, 1H);6.35-6.60 (m, 1H); 7.10-7.50 (m, 5H).

Hydrochloride: mp=112° C. (ethyl ether).

Analysis (C₁₈ H₂₆ ClN): % C, H, Cl, N in agreement;

IR (KBr): 3400, 2800, 2600, 2500, 1440, 1200, 1020, 1000, 960, 800, 770,680 cm⁻¹.

Example 2B.1 (E)-2-(p-fluorocinnamyl)-1-cyclopropylmethyl-pyrrolidine(formula I-E; Ar=p-fluorophenyl, m=1, n=2, R=cyclopropyl)

In a reactor protected from moisture, there are introduced 2.3 g (0.010mol) of (E)-2-(p-fluorocinnamyl)piperidine (Preparation 2B) dissolved in25.2 ml acetonitrile, followed, during 2 min, by 1.56 g (1.1 ml-0.012mol) bromomethylcyclopropane. The medium is kept stirring at ambienttemperature for 1 h 30 min, is raised to 60° C. for 4 h, and is thenlowered to 20°±3° C. for 16 h. The solvent is evaporated under vacuumand on a water bath. The oily residue is dissolved in water, acidifiedand extracted with ether. After decanting, the cooled aqueous phase isalkalinized with soda, extracted with ether and washed with saturatedNaCl solution. The organic phase is dehydrated over Na₂ SO₄ and thesolvent is then removed by distillation. The residue is purified by theChromatoflash technique, elution being carried out with a 90:10 v/vmixture of methylene chloride and 10% ammoniacal MeOH, and is thensubjected to a second acid-alkali treatment. (E)-2-(p-fluorocinnamyl)-1-(cyclopropylmethyl)pyrrolidine is obtained inthe form of a yellow oil.

Weight: 0.9 g Yield: 31%

TLC: Rf=0.35-0.60 (90:10 v/v methylene chloride/10% ammoniacal MeOH)

NMR: 0.00-0.20 (m, 2H); 0.40-0.60 (m, 2H); 0.70-1.00 (m, 1H); 1.10-1.90(m, 6H); -2.00-2.70 sic! (m, 6H); 2.8 sic!-3.20 (m, 1H); 5.90-6.50 (m,2H) 6.80-7.40 (m, 4H).

Hydrochloride: mp=135° C. (ethyl acetate)

Analysis (C₁₈ H₂₅ ClFN): % C, H, Cl, F, N in agreement;

IR (KBr): 3500, 2850, 2450, 1590, 1500, 1450, 1220, 1000, 860, 520 cm⁻¹.

Example 2B.2 (Z)-2-(p-fluorocinnamyl)-1-cyclopropylmethylpiperidine(formula I-Z; Ar=p-fluorophenyl, m=1, n=2, R=cyclopropyl)

The compound is prepared as described in Example 2B.1 above from(Z)-2-(p-fluorocinnamyl)piperidine (Preparation 2B), with a yield of43%.

TLC: Rf=0.35-0.60 (90:10 v/v methylene chloride/10% ammoniacal MeOH)

NMR: 0.00-0.10 (m, 2H); 0.20-0.60 (m, 2H); 0.60-1.00 (m, 1H); 1.10-1.80(m, 6H); 2.00-2.60 (m, 6H); 2.80-3.20 (m, 1H); 5.50-5.90 (m, 1H);6.30-6.60 (m, 1H); 6.90-7.30 (m, 4H).

Hydrochloride: mp=102° C. (ethyl acetate)

Analysis (C₁₈ H₂₅ ClFN): % C, H, Cl, F, N in agreement;

IR (KBr): 3400, 2900, 2400, 1600, 1500, 1440, 1220, 1160, 1000, 1090,1030, 860, 840, 750, 620, 520 cm⁻¹.

Example 2C (E)-2-(p-chlorocinnamyl)-1-(cyclopropylmethyl)piperidine (f.I; Ar=p-chlorophenyl, m=1, n=2, R=cyclopropyl)

The compound is prepared as described in Example 2B.1 above, from(E)-2-(p-chlorocinnamyl)piperidine (Preparation 2C) with a yield of 44%.

NMR: 0.00-0.20 (m, 2H); 0.40-0.60 (m, 2H); 0.60-1.00 (m, 1H); 1.10-1.80(m, 6H); 2.10-2.80 (m, 6H); 2.90-3.20 (m, 1H); 5.90-6.70 (m, 2H); 7.30(m, 4H).

Hydrochloride: mp=173° C. (ethyl acetate)

Analysis (C₁₈ H₂₅ Cl₂ N): % C, H, Cl, N in agreement;

IR (KBr): 3500, 2900, 2500, 1440, 1080, 970, 950, 850 cm⁻¹.

Example 2D (E)-2-(m-chlorocinnamyl)-1-(cyclopropylmethyl)piperidine(formula I; Ar=m-chlorophenyl, m=1, n=2, R=cyclopropyl)

The compound is prepared as described in Example 1.1 from(E)-2-(m-chlorocinnamyl) piperidine (Preparation 2D).

Stage a) (E)-2-(m-chlorocinnamyl)-1-(cyclopropanecarbonyl)piperidine(formula II; Ar=m-chlorophenyl, m=1, n=2, R=cyclopropyl). Yield: 91%.

Stage b) (E)-2(m-chlorocinnamyl)-1-(cyclopropylmethyl)piperidine. Yield:95%.

TLC: Rf=0.7 (90:10 v/v methylene chloride/10% ammoniacal MeOH)

NMR: 0.00-0.30 (m, 2H); 0.60-0.70 (m, 2H); 0.90-1.10 (m, 1H); 1.30-1.90(m, 6H); 2.30-2.80 (m, 6H); 3.10-3.20 (m, 1H); 6.30-6.50 (m, 2H);7.20-7.50 (m, 4H).

Hydrochloride: mp=129° C. (ethyl acetate).

Analysis (C₁₈ H₂₅ Cl₂ N): % C, H, Cl, N in agreement;

IR (KBr): 3400, 2950, 2500, 1590, 1560, 1440, 1210, 970, 780, 680, 560cm⁻.

Example 2E (E)-2-(3,4-dichlorocinnamyl)-1-(cyclopropylmethyl)piperidine(formula I; Ar=3,4-dichlorophenyl, m=1, n=2, R cyclopropyl)

The compound is prepared as described in Example 1.1, from(E)-2-(3,4-dichlorocinnamyl) piperidine (Preparation 2E).

Stage a) (E)-2-(3,4-dichlorocinnamyl)-1-(cyclopropanecarbonyl)piperidine(formula II; Ar=3,4-dichlorophenyl, m=1, n=2, R=cyclopropyl). Yield:91%.

TLC: Rf=0.90-1.00 (90:10 v/v methylene chloride/10% ammoniacal MeOH).

Stage b) (E)-2-(3,4-dichlorocinnamyl)-1-(cyclopropylmethyl)piperidine.Yield: 79%.

TLC: Rf=0.65-0.80 (90:10 v/v methylene chloride/10% ammoniacal MeOH).

NMR: 0.00-0.20 (m, 2H); 0.40-0.70 (m, 2H); 0.70-1.10 (m, 1H); 1.10-1.80(m, 6H); 2.10-2.80 (m, 6H); 2.90-3.20 (m, 1H); 6.20-6.40 (m, 2H);7.10-7.50 (m, 3H).

Hydrochloride: mp=153° C. (ethyl acetate)

Analysis (C₁₈ H₂₄ Cl₃ N): % C, H, Cl, N in agreement;

IR (KBr): 3400, 2900, 2500, 1450, 1130, 1020, 990, 820, 800 cm⁻¹.

Example 2F (E)-2-(p-methylcinnamyl)-1-(cyclopropylmethyl)piperidine(formula I; Ar=p-toluyl, m=1, n=2, R=cyclopropyl)

The compound is prepared as described in Example 1.1, from(E)-2-(p-methylcinnamyl)piperidine (Preparation 2F).

Stage a) (E)-2-(p-methylcinnamyl)-1-(cyclopropane)carbonylpiperidine(formula II; Ar=p-toluyl, m=1, n=2, R=cyclopropyl). Yield: 100%.

Stage b) (E)-2-(p-methylcinnamyl)-1-(cyclopropylmethyl)piperidine.Yield: 98%.

NMR: 0.00-0.20 (m, 2H); 0.40-0.60 (m, 2H); 0.70-1.10 (m, 1H); 1.10-1.90(m, 6H); 2.35 (s, 3H); 2.10-2.80 (m, 6H); 2.80-3.20 (m, 1H); 5.90-6.50(m, 2H); 6.90-7.30 (m, 4H).

Hydrochloride: mp=152° C. (ethyl acetate).

Analysis (C₁₉ H₂₈ ClN).: % C, H, Cl, N in agreement;

IR (KBr): 3300, 2900, 2500, 1500, 1450, 1420, 1250, 1020, 960, 800, 490cm⁻¹.

Example 2G(E)-2-(p-trifluoromethylcinnamyl)-1-cyclopropylmethylpiperidine (formulaI; Ar=p-trifluoromethylphenyl, m=1, n=2, R=cyclopropyl)

The compound is prepared as described in Example 1.1, from(E)-2-(p-trifluoromethylcinnamyl)piperidine (Preparation 2G).

Stage a) (E)-2-(p-trifluoromethylcinnamyl)-1-cyclopropanecarbonylpiperidine (formulaII; Ar=p-trifluoromethylphenyl, m=1, n=2, R=cyclopropyl). Yield: 98%.

Stage b)(E)-2-(p-trifluoromethylcinnamyl)-1-cyclopropylmethylpiperidine. Yield;92%.

TLC: Rf=0.6 (90:10 v/v methylene chloride/10% ammoniacal MeOH)

NMR: 0.00-0.20 (m, 2H); 0.40-0.60 (m, 2H); 0.80-1.00 (m, 1H); 1.20-1.80(m, 6H); 2.30-2.70 (m, 6H); 3.00-3.10 (m, 1H); 6.20-6.40 (m, 1H) 6.45(d, 1H); 7.30-7.70 (m, 4H).

Hydrochloride: mp=125° C. (ethyl acetate).

Analysis (C₁₉ H₂₅ F₃ ClN): % C, H, F, Cl, N in agreement;

IR (KBr): 2950, 2450, 1430, 1320, 1160, 1120, 1070, 960, 790, 690 cm⁻¹.

Example 2H (E) -2-(p-methoxycinnamyl)-1-cyclopropylmethylpiperidine(formula I; Ar=p-methoxyphenyl, m=1, n=2, R=cyclopropyl)

The compound is prepared as described in Example 1.1, from (E)-2-(p-methoxycinnamyl)piperidine (Preparation 2H).

Stage a) (E)-2-(p-methoxycinnamyl)-1-cyclopropanecarbonylpiperidine(formula II; Ar=p-methoxyphenyl, m=1, n=2, R=cyclopropyl). Yield: 90%.

TLC: Rf=0.90-1.00 (90:10 v/v methylene chloride/10% ammoniacal MeOH)

Stage b) (E)-2-(p-methoxycinnamyl)-1-cyclopropylmethylpiperidine. Yield:72%.

TLC: Rf=0.80-1.00 (90:10 v/v methylene chloride/10% ammoniacal MeOH)

A final purification step is added, by the Chromatoflash technique on asilica column, with elution by means of a 95:5 v/v mixture of methylenechloride and 10% ammoniacal methanol.

NMR: 0.10-0.30 (m, 2H); 0.40-0.70 (m, 2H); 0.70-1.10 (m, 1H); 1.20-2.00(m, 6H); 2.00-2.80 (m, 6H); 2.80-3.20 (m, 1H); 3.75 (s, 3H); 5.90-6.50(m, 2H); 6.70-7.00 (m, 2H); 7.20-7.40 (m, 2H).

Analysis (C₁₉ H₂₇ NO): % C, H, N, 0 in agreement;

IR (NaCl): 2800, 1600, 1500, 1450, 1260, 1170, 1050, 980, 820 cm⁻¹.

Example 2I(E)-2-(1-naphth-1-yl-propen-3-yl)-1-cyclopropylmethylpiperidine (formulaI; Ar=naphth-1-yl, m=1, n=2, R=cyclopropyl)

The compound is prepared as described in Example 1.1 from(E)-2-(1-naphth-1-yl-propen-3-yl)piperidine (Preparation 2I).

Stage a)(E)-2-(1-naphth-1-yl-propen-3-yl)-1-cyclopropanecarbonylpiperidine(formula II; Ar=naphth-1-yl, m=1, n=2, R=cyclopropyl). Yield: 99%.

Stage b)(E)-2-(1-naphth-1-yl-propen-3-yl)-1-cyclopropylmethylpiperidine. Yield:92%.

TLC: Rf=0.75 (90:10 v/v methylene chloride/10% ammoniacal MeOH)

NMR: 0.00-0.20 (m, 2H); 0.40-0.60 (m, 2H); 0.80-1.00 (m, 1H); 1.10-1.40(m, 1H); 1.40-1.90 (m, 5H); 2.30-2.80 (m, 6H); 3.00-3.20 (m, 1H);6.10-6.30 (m, 1H); 7.10 (d, 1H); 7.30-7.60 (m, 4H); 7.70-7.90 (m, 2H);8.10 (d, 1H).

Hydrochloride: mp=118° C. (ethyl acetate).

Analysis (C₂₂ H₂₈ ClN): % C, H, Cl, N in agreement;

IR (KBr): 3400, 2950, 2450, 1450, 1430, 1210, 1020, 980, 880, 500 cm⁻¹.

Example 2J(E)-2-(1-thien-2-yl-propen-3-yl)-1-cyclopropylmethylpiperidine (formulaI; Ar=thien-2-yl, m=1, n=2, R=cyclopropyl)

The compound is prepared as described in Example 1.1 from (E)-2-(1-thien-2-yl-propen-3-yl)piperidine (Preparation 2J).

Stage a) (E)-2-(1-thien-2-yl-propen-3-yl)-1-cyclopropanecarbonylpiperidine (formulaII; Ar=thien-2-yl, m=1, n=2, R=cyclopropyl). Yield: 96%.

Stage b) (E)-2-(1-thien-2-yl-propen-3-yl)-1-cyclopropylmethylpiperidine.Yield: 76%.

TLC: Rf=0.8 (90:10 v/v methylene chloride/10% ammoniacal MeOH)

A purification step is added, by the Chromatoflash technique on a silicacolumn, with elution by means of a 95:5 v/v mixture of methylenechloride and 10% ammoniacal methanol.

NMR: 0.00-0.20 (m, 2H); 0.50-0.60 (m, 2H); 0.80-0.90 (m, 1H); 1.20-1.80(m, 6H); 2.20-2.60 (m, 6H); 3.00-3.10 (m, 1H); 6.00-6.10 (m, 1H); 6.50(d, 1H); 6.80-7.00 (m, 2H); 7.10 (d, 1H).

Hydrochloride: mp=175°-177° C. (ethyl acetate).

Analysis (C₁₆ H₂₄ CLNS): % C, H, Cl, N, S in agreement;

IR: 2980, 2500, 1470, 1210, 980, 830, 740, 560 cm⁻¹.

Example 2K (Z)-2-cinnamyl-1-cyclopropylmethylpyrrolidine (formula I-Z;Ar=phenyl, m=1, n=1, R=cyclopropyl)

The compound is prepared as described in Example 1.1 from(Z)-2-(cinnamyl)pyrrolidine (Preparation 2K).

Stage a) (Z)-2-cinnamyl-1-(cyclopropanecarbonyl)pyrrolidine (formula II;Ar=phenyl, m=1, n=1, R=cyclopropyl). Yield: 87%.

TLC: Rf=0.35-0.55 (95:5 v/v methylene chloride/acetone)

Stage b) (Z)-2cinnamyl-1(cyclopropylmethylprrolidine. Yield: 97%.

A purification step is added, by the Chromatoflash technique on a silicacolumn, with elution by means of a 96:4 v/v mixture of methylenechloride and ammoniacal methanol.

TLC: Rf=0.50-0.80 (98:2 v/v methylene chloride/10% ammoniacal MeOH)

NMR: 0.00-0.20 (m, 2H); 0.40-0.60 (m, 2H); 0.80-0.90 (m, 1H); 1.50-2.00(m, 5H); 2.10-2.20 (m, 1H); 2.30-2.40 (m, 2H); 2.60-2.80 (m, 2H);3.80-3.90 (m, 1H); 5.60-5.70 (m, 1H); 6.50 (s,1H); 7.10-7.30 (m, 5H).

Hydrochloride: mp=129° C. (ethyl ether/isopropanol).

Analysis (C₁₇ H₂₄ ClN): % C, H, Cl, N in agreement;

IR (KBr): 2900, 2480, 1440, 1180, 1060, 940, 800, 700, 500 cm⁻¹.

Example 2L (E)-2-(p-fluorocinnamyl)-1-cyclopropylmethylpyrrolidine(formula I; Ar=p-fluorophenyl, m=1, n=1, R=cyclopropyl)

The compound is prepared as described in Example 1.1, from(E)-2-(p-fluorocinnamyl)pyrrolidine (Preparation 2L).

Stage a) (E)-2-(p-fluorocinnamyl)-1-cyclopropanecarbonylpyrrolidine.(formula II; Ar=p-fluorophenyl, m=1, n=2, R=cyclopropyl). Yield: 100%.

TLC: Rf=0.400-0.55 (95:5 v/v methylene chloride/acetone)

Stage b) (E)-2-(p-fluorocinnamyl)-1-cyclopropylmethylpyrrolidine. Yield:84%.

TLC: Rf=0.75-0.95 (90:10 v/v methylene chloride/10% ammoniacal MeOH)

NMR: 0.10-0.20 (m, 2H); 0.40-0.60 (m, 2H); 0.90-1.00 (m, 1H); 1.50-2.10(m, 5H); 2.10-2.30 (m, 2H); 2.30-2.40 (m, 1H); 2.50-2.60 (m, 1H);2.70-2.80 (m, 1H): 3.30-3.40 (m, 1H): 6.00-6.20 (m, 1H):

6.40 (d, 1H); 6.90-7.00 (m, 2H); 7.20-7.30 (m, 2H).

IR (NaCl): 2950, 2850, 1600, 1500, 1220, 1160, 980, 840 cm⁻¹.

Hydrochloride: The hydrochloride is very hygroscopic.

Analysis (C₁₇ H₂₃ ClFN): % C, H, F, N in agreement.

Pharmacological Studies

The compounds of the invention (I) and their salts show their capacityfor interaction with sigma receptors in binding tests carried out invitro in the presence of a labeled ligand specific for sigma receptors,(+) ³ H!SKF10.047. The test of binding to phenylcyclidine receptors (PCPreceptors), performed in the presence of a ligand specific for PCPreceptors, ³ H!TCP, was used to investigate any undesirable interactionof the compounds of the invention with these receptors.

In vivo, the ability of the compounds of the invention (I) to inhibitgastroduodenal ulcers induced by the administration of cysteamine wasdemonstrated, and in a very favorable manner, by comparison withIgmesine hydrochloride (proposed INN), or(+)-N-(cyclopropylmethyl)-1-ethyl-N-methyl-1,4-diphenyl-3-butene-1-ylaminehydrochloride, a preferred compound of Patent EP 362,001.

In addition, the protection afforded by the compounds of the inventionagainst diarrhea induced experimentally by a bacterial endotoxin,Salmonella lipopolysaccharide, was demonstrated in the mouse.

In vitro Study

Experiments on binding to sigma and PCP receptors are performed with theligands (+) ³ H!SKF10.047 and ³ H!TCP, respectively, by the techniquedescribed by Largent, B. L., et al. in J. Pharmacol. Exp. Ther., 1986,Vol. 238, pp. 739-748. The principle of this technique is to place incompetition the affinity of the test substance and that of a radioactiveligand specific for the receptor being studied.

The technique consists in incubating a preparation of rat brain membraneloaded with the labeled ligand specific for the receptor under study insolutions of varying concentration of the test substance. Afterfiltration, one measures the radioactivity of the solution, whichrepresents the displacement of this labeled ligand by the testsubstance.

The results are expressed as the IC₅₀ of the test substance, which isthe concentration at which the tritiated ligand is displaced from 50% ofits binding sites in the membrane preparation used. Thus, the lower theIC₅₀, the greater the affinity of the compound for the receptor. Thevalues obtained are presented in Table 1 below. Haloperidol (INN), whichis known, among other properties, for its affinity for σ receptors, isshown by way of reference.

                  TABLE 1                                                         ______________________________________                                        IN VITRO BINDING TESTS: IC.sub.50 (nM)                                        Receptors        Sigma   PCP                                                  ______________________________________                                        Test substances                                                               Example 1.1      34.25   >10,000                                              Example 1.4      4.52    >10,000                                              Example 2A.6     34.3    >10,000                                              Haloperidol      8.95    1.268                                                ______________________________________                                    

These results show that the compounds (I) of the invention have a strongaffinity for sigma receptors, especially in the case of the compound ofExample 1.4. In addition, in comparison to haloperidol, the compounds(I) of the invention show an affinity for PCP receptors that may beregarded as zero.

In a second series of experiments, the IC₅₀ of other compounds of theinvention was determined with regard to ³ H!SKF10.047 in rat brainmembranes and this value was compared with the IC₅₀ of haloperidol,based on the ratio of the IC₅₀ of haloperidol to the IC₅₀ of thecompound under test. The results are given in Table 2.

                  TABLE 2                                                         ______________________________________                                        IN VITRO SIGMA BINDING TESTS                                                  IN COMPARISON TO HALOPERIDOL                                                  Compounds                                                                              IC.sub.50, haloperidol                                                                     Compounds  IC.sub.50, haloperidol                       tested   IC.sub.50, example                                                                         tested     IC.sub.50, example                           ______________________________________                                        Ex. 1.3  1.6          Ex. 2A.5   1.0                                          Ex. 1.5  0.8          Ex. 2B.2   1.6                                          Ex. 1.6  1.3          Ex. 2G     0.8                                          Ex. 2A.3 1.4          Ex. 2K     4.3                                          Ex. 2A.4 2.3          Ex. 2L     1.1                                          ______________________________________                                    

These results confirm that the compounds (I) of the invention have astrong affinity for sigma receptors characterized by ³ H!SKF10.047,equal to or greater than that of haloperidol and in some casesapproximately 2 to 4 times greater.

In conclusion, these results provide convincing evidence of the highaffinity of the compounds of the invention for sigma receptors. Thisaffinity is, moreover, accompanied by a remarkable specificity, sincethese compounds, unlike haloperidol, do not interfere with PCPreceptors.

In vivo Study: Cysteamine-induced Gastroduodenal Ulcer

The activity of the compounds of the invention with respect to thegastrointestinal tract was shown in the rat by their ability to inhibitgastroduodenal ulcers induced by the administration of cysteamine. Interms of practical methodology, the study is performed according to themethod described by Robert, A., et al., in Digestion, 1974, Vol. 11, pp.199-214, in groups of male Sprague-Dawley rats with an average weight of200 g, to which a cysteamine hydrochloride solution is administered bysubcutaneous injection in a dose of 400 mg/kg. The test compounds areadministered to the animals 1 h or 30 min, respectively, before theulcerogenic agent, depending on whether the oral or intraperitonealroute is used. Eighteen hours later, the rats are sacrificed byelongation; the stomach and duodenum are removed, rinsed withphysiological salt solution, and pinned to a card. Theantropyloroduodenal region is examined for ulcers, and the area of theulcers, expressed in mm², is determined by multiplying the two mainperpendicular axes of the lesion. Statistical analysis of the results isperformed by means of Student's t-test for the ulcerated areas incomparison with a control group. The results obtained afterintraperitoneal administration are presented in Table 3 and areexpressed as the ED₅₀, which is the effective dose (mg/kg) of compoundinhibiting 50% of the cysteamine-induced ulcers. Igmesine is presentedby way of comparison.

                  TABLE 3                                                         ______________________________________                                        CYSTEAMINE-INDUCED ULCER: ED.sub.50 BY THE I.P. ROUTE                         Compounds tested       Compounds tested                                       (mg/kg)       ED.sub.50                                                                              (mg/kg)       ED.sub.50                                ______________________________________                                        Example 1.1   0.185    Example 2A.1  0.100                                    Example 1.2   <0.100   Example 2A.2  <0.100                                   Example 1.3   <0.100   Example 2A.6  <0.100                                   Example 1.4   0.137    Igmesine      5.950                                    ______________________________________                                    

The compounds of the invention are conclusively demonstrated to be 30 to60 times more active than this compound of prior art to which they arecompared.

Diarrhea Induced by salmonella ipopolysaccharide

The activity of the compounds of the invention in a model of secretorydiarrhea induced by Salmonella enteritidis lipopolysaccharide (LPS) wasstudied according to a protocol inspired by Ciancio, M. J., et al.,Gastroenterology, 1992, Vol. 103, pp. 1437-1443. Male dBA₂ mice rangingin weight from 20 to 25 g, placed in individual grid-bottomed cages,were administered the test compound orally 1 h after the injection of S.enteritidis LPS (Ref. L6761 Sigma) in a dose of 15 mg/kg i.v. Apreweighed filter paper was placed under each cage in order to weigh thefeces eliminated over a period of 2 h. The ED₅₀ was calculated, thisbeing the dose that reduced the increase in feces caused by the LPS by50% in comparison with a control group given the endotoxin alone.

The tested compounds (I) of the invention showed especially advantageousactivity in this model, with ED₅₀ s that were generally below 100 μg/kg.

These results point to the potential use of the compounds of theinvention for the symptomatic treatment of diarrheas with a secretorycomponent and of diverse etiologies: toxic, infectious including viral,inflammatory, and post-antibiotic, as well as diarrheas followingorganic disease of the mucosa.

The acute toxicity of the compounds of the invention was determinedafter oral administration in the rat. On this basis it was possible todetermine their approximate LD₅₀, which is the lethal dose for 50% ofthe animals under the conditions of the experiment. This toxicity wasconsidered to be negligible at doses more than one hundred times thephysiologically active dose of these compounds.

Formulations

As described, these pharmacological properties combined with the lowtoxicity of the compounds of the invention make it possible to envisiontheir usefulness as medicinal drugs for the prevention or treatment ofi) neurological disorders, especially psychotic states, depressivestates, memory and behavioral disturbances, stress and anxiety, as wellas ii) disorders of the gastrointestinal tract, such as, for example,certain forms of gastroduodenal ulcer, or diarrhea, especially with asecretory component.

The dosages normally range from 0.1 to 1000 mg, and more especially 1 to500 mg, of compound, depending on the nature and severity of thecomplaint to be treated. These daily therapeutic doses may be dividedinto several portions. Generally speaking, a daily dosage of 5 mg to 250mg of compound, divided into two to four portions, yields a satisfactorytherapeutic result.

The compounds of the invention are administered to the patients to betreated in the form of medications whose nature is suited to thecomplaint to be treated.

The medicinal preparations will be, as non-restrictive examples,tablets, dragees, capsules, powders, solutions, suspensions, gels orsuppositories, depending on the case. These various pharmaceuticaldosage forms are prepared from the compounds in base form or in the formof their salts and according to methods commonly employed inpharmaceutical practice.

Generally, in medicinal forms of a "solid" nature, the active principlerepresents from 2 to 50% by weight of the total of the finished dosageform, while the excipients represent from 98 to 50%. For "liquid" dosageforms or those which may be considered liquid, the amount of activeprinciple is between 0.1 and 10% by weight of the finished dosage form,while the excipients may represent 99.9 to 90% by weight of this dosageform.

The formula and the preparation of tablets and of isotonic solution withthe compounds of Example 1.4 are described by way of illustration.

Tablets

Formula

    ______________________________________                                        Active principle (compound of Example 1.4)                                                            5.0 to 25.0                                                                            mg                                           Polyvinylpyrrolidone    20.0     mg                                           Carboxymethyl starch    8.0      mg                                           Magnesium stearate      2.0      mg                                           Colioidal silica        0.4      mg                                           Lactose, sufficient quantity for                                                                      200.0    mg                                           ______________________________________                                    

Preparation

The active principle, in aqueous alcohol solution, is mixed with lactoseand then granulated with polyvinylpyrrolidone, also in solution. Theparticles are dried and sieved through a screen with a mesh opening of 1mm. The carboxymethyl starch is mixed with the colloidal silica and thenadded to the granules. This mixture is then mixed intimately with themagnesium stearate and tableted in a dose of 200.0 mg per tablet.

Injectable isotonic solution

Formula

    ______________________________________                                        Active substance (I), the hydrochloride of Ex. 1.4                                                      10.0   mg                                           Sodium chloride           9.0    mg                                           Distilled water, sufficient quantity for                                                                1.0    ml                                           ______________________________________                                    

Preparation

The isotonic solution is distributed in ampuls of suitable volume,which, after sealing, are sterilized by customary thermal means, oralternatively the solution is sterilized by filtration and distributedin ampuls which are then sealed, all of these operations being carriedout in a sterile atmosphere.

What is claimed is:
 1. A sigma receptor ligand comprising a2-(arylalkenyl) azacycloalkane compound of formula (I): ##STR13## inwhich: Ar is aryl or heteroaryl, optionally mono-, di- ortri-substituted with a halogen, nitro, lower alkyl, lower haloalkyl,lower alkoxy or lower haloalkoxy group;m has the value of 1 or 2; n hasthe value of 1 to 3; R is phenyl, optionally substituted with a halogen,nitro, lower alkyl, lower haloalkyl, lower alkoxy or lower haloalkoxygroup or a cycloalkyl group containing 3 to 7 carbon atoms, an opticalor geometric isomer thereof, a derivative in which an atom is replacedby an radioactive isotope, and an addition salt with a pharmaceuticallyacceptable acid.
 2. The sigma ligand receptor according to claim 1,characterized in that Ar represents a phenyl radical, optionallysubstituted.
 3. The sigma ligand receptor according to claim 1,characterized in that n has the value of 1 or
 2. 4. The sigma ligandreceptor according to claim 1, characterized in that R is phenyl,cyclopropyl or cyclobutyl.
 5. A process for the preparation of a2-(arylakenyl) azacycloalkane (I) compound according to claim 1,characterized in that it comprises:acylation of an intermediateazacycloalkane (III) ##STR14## in which n and Ar are as defined for (I),with a reactant (IV): ##STR15## in which m and R are as defined for (I)and X is --OH or a halogen, to obtain an intermediate carboxamidederivative (II): ##STR16## followed by reduction of the carboxamide (II)with a metal hydride or an organometallic hydride.
 6. A pharmaceuticalproduct comprising a sigma ligand receptor according to claim 1 as anactive ingredient in a therapeutically effective amount and incombination with a pharmaceutically acceptable excipient.
 7. The productaccording to claim 6 wherein the active ingredient is present in anamount of between about 2 and 50% by weight and the excipient is presentin an amount of between about 50 and 98% by weight, said product beingin the form of a solid.
 8. The product according to of claim 6 whereinthe active ingredient is present in an amount of between about 0.1 and10% by weight while the excipient is present in an amount of betweenabout 90 and 99.9% by weight, said product being in the form of aliquid.
 9. A method for treating ulcers of the gastrointestinal tractwhich comprises administering to a subject in need of such treatment atherapeutically effective amount of a 2-(arylalkenyl) azacycloalkanecompound according to claim
 1. 10. A method for treating ulcers of thegastrointestinal tract which comprises administering to a subject inneed of such treatment a therapeutically effective amount of a2-(arylalkenyl) azacycloalkane compound in the form of thepharmaceutical product of claim 6.